RNA: A New Method To Discover Its High-resolution Structure (Chemistry)

New SISSA research combines experimental data and molecular dynamics simulations to study biomolecules in their natural environment

The structure of a biomolecule can reveal much about its functioning and interaction with the surrounding environment. The double-helical structure of DNA and its implications for the processes of transmission of genetic information form an obvious example. In a new study by SISSA, published in Nucleic Acids Research, experimental data were combined with computer simulations of molecular dynamics to examine the conformation of an RNA fragment involved in protein synthesis and its dependence on the salts present in the solution. The research has led to a new method for high-resolution definition of the structures of biomolecules in their physiological environments.

“X-ray crystallography, as used to discover the double-helical conformation of DNA, remains one of the most common techniques for studying biomolecule structures”, explains SISSA physicist Giovanni Bussi. “This technique allows us to reconstruct the image of the molecule in solid state crystalline form. However, this yields a static view of the structure that may not correspond to that assumed in the aqueous natural environment in which biomolecules are normally found.”

This is why researchers began to use the small-angle X-ray scattering (SAXS) technique in the last decade to study RNA molecules, which can have highly dynamic structures. This method can be used directly in aqueous solutions that reproduce the physiological environment. Furthermore, the composition of the solutions can be modified to study how the molecules adapt to different conditions. Unfortunately, however, SAXS has limited resolution, in the order of a nanometer. Giovanni Bussi and Mattia Bernetti, a research fellow at SISSA, therefore decided to enhance SAXS via a ‘computational microscope’, combining it with molecular dynamics simulations that allow computerised reconstruction of molecular structures at the atomic level.

“We studied a fragment of ribosomal RNA involved in protein synthesis,” explain the researchers. “We used SAXS data, derived from aqueous solutions containing different mixtures of salts, that was provided by Kathleen B. Hall of the Washington University School of Medicine in St Louis, and combined them with molecular dynamics simulations. By this means we discovered the existence of two distinct conformations: one more compact and functional to the protein synthesis process, the other more extended, confirming the dynamic nature of RNA. In particular, we noticed how the prevalence of one structure over the other varies with the salts dissolved in solution, further underlining the importance of studying these molecules in an environment as similar as possible to that of the cell.”

Bernetti and Bussi conclude that the results of the study, published in Nucleic Acids Research, have significance beyond the specific case and indicate an innovative method offering two advantages: “In this work, we combined molecular dynamics simulations and SAXS experimental data to obtain high-resolution structures of RNA biomolecules. This is a useful approach in two senses: on one hand, it allows detail to be added to SAXS experimental data, which in fact give a very approximate view; on the other hand, it allows results of molecular dynamics to be corrected if the models used in the simulations are insufficiently accurate.”

Video interview with Mattia Bernetti available at https://youtu.be/jvEAgSjgm4c

Reference: Mattia Bernetti, Kathleen B Hall, Giovanni Bussi, Reweighting of molecular simulations with explicit-solvent SAXS restraints elucidates ion-dependent RNA ensembles, Nucleic Acids Research, 2021;, gkab459, https://doi.org/10.1093/nar/gkab459

Provided by SISSA

Insulators Turn Up The Heat On Quantum Bits (Quantum)

Quantum technologies are based on quantum properties of light, electrons, and atoms. In recent decades, scientists have learned to master these phenomena and exploit them in applications. Thus, the construction of a quantum computer for commercial applications is also coming within reach. One of the emerging technologies that is currently being advanced very successfully is ion trap quantum computers. Here, charged particles are trapped with electromagnetic fields in a vacuum chamber and prepared in such a way that they can serve as carriers for information and be used for computing, which includes cooling them to the lowest temperatures permitted by quantum mechanics. However, the quantum mechanical properties exploited in this process are highly error prone. Even the smallest deficiencies can heat up the strongly cooled particles and thereby lead to errors in the processing of quantum information. Possible sources of such faults are weakly conducting or non-conducting materials, which are used, for example, as insulators in a metallic ion trap, or optics, which are necessary for coupling ions with laser light. “Even for ion traps made exclusively of metal, oxide layers on the metals would cause such failures,” explains Tracy Northup at the Department of Experimental Physics of the University of Innsbruck in Austria. Northups team together with collaborators in Innsbruck and in the U.S. have found a way to determine the influence of dielectric materials on the charged particles in ion traps.

Experimentally confirmed

This was achieved because the Innsbruck quantum physicists have an ion trap in which they can precisely set the distance between the ions and dielectric optics. Based on an earlier proposal by Rainer Blatt’s group, the physicists computed the amount of noise caused by the dielectric material for this ion trap and compared it with data from experiment. “Theory and experiment agree very well, confirming that this method is well suited for determining the influence of dielectric materials on the ions,” explains Markus Teller from the Innsbruck team. To calculate the noise, the so-called fluctuation-dissipation theorem from statistical physics was used, which mathematically describes the response of a system in thermal equilibrium to a small external perturbation.

View into the vacuum chamber where the ion trap is isolated from external noise. © University of Innsbruck

“In quantum computers, there are many possible sources of noise, and it is very difficult to sort out the exact sources,” says Tracy Northup. “Our method is the first to quantify the influence of dielectric materials in a given ion trap on the charged particles. In the future, designers of ion trap quantum computers will be able to assess this effect much more accurately and design their devices to minimize these perturbations.” After having successfully demonstrated the method on their own ion trap, the Innsbruck physicists now want to apply it to the ion traps of collaborators in the U.S. and Switzerland.

The research was financially supported by the Austrian Science Fund FWF and the European Union, among others. The results have been published in the journal Physical Review Letters.

Featured image: In the ion trap, the distance between the ions and optics can be precisely adjusted. © University of Innsbruck

Publication: Heating of a trapped ion induced by dielectric materials. Markus Teller, Dario A. Fioretto, Philip C. Holz, Philipp Schindler, Viktor Messerer, Klemens Schüppert, Yueyang Zou, Rainer Blatt, John Chiaverini, Jeremy Sage, and Tracy E. Northup. Phys. Rev. Lett. 126, 230505 doi: 10.1103/PhysRevLett.126.230505

Provided by University of Innsbruck

Black Holes Help With Star Birth (Planetary Science)

The cosmic mass monsters clear the way for the formation of new suns in satellite galaxies

Research combining systematic observations with cosmological simulations has found that, surprisingly, black holes can help certain galaxies form new stars. On scales of galaxies, the role of supermassive black holes for star formation had previously been seen as destructive – active black holes can strip galaxies of the gas that galaxies need to form new stars. The new results, published in the journal Nature, showcase situations where active black holes can, instead, “clear the way” for galaxies that orbit inside galaxy groups or clusters, keeping those galaxies from having their star formation disrupted as they fly through the surrounding intergalactic gas.

Active black holes are primarily thought to have a destructive influence on their surroundings. As they blast energy into their host galaxy, they heat up and eject that galaxy’s gas, making it more difficult for the galaxy to produce new stars. But now, researchers have found that the same activity can actually help with star formation – at least for the satellite galaxies that orbit the host galaxy.

The counter-intuitive result came out of a collaboration sparked by a lunchtime conversation between astronomers specializing in large-scale computer simulations and observers. As such, it is a good example for the kind of informal interaction that has become more difficult under pandemic conditions. 

Astronomical observations that include taking a distant galaxy’s spectrum – the rainbow-like separation of a galaxy’s light into different wavelengths – allow for fairly direct measurements of the rate at which that galaxy is forming new stars. 

Going by such measurements, some galaxies are forming stars at rather sedate rates. In our own Milky Way galaxy, only one or two new stars are born each year. Others undergo brief bursts of excessive star formation activity, called “star bursts”, with hundreds of stars born per year. In yet other galaxies, star formation appears to be suppressed, or “quenched,” as astronomers say: Such galaxies have virtually stopped forming new stars.

A special kind of galaxy, specimens of which are frequently – almost half of the time – found to be in such a quenched state, are so-called satellite galaxies. These are part of a group or cluster of galaxies, their mass is comparatively low, and they orbit a much more massive central galaxy similar to the way satellites orbit the Earth. 

Such galaxies typically form very few new stars, if at all, and since the 1970s, astronomers have suspected that something very much akin to headwind might be to blame: Groups and clusters of galaxies not only contain galaxies, but also rather hot thin gas filling the intergalactic space. 

As a satellite galaxy orbits through the cluster at a speed of hundreds of kilometers per second, the thin gas would make it feel the same kind of “headwind” that someone riding a fast bike, or motor-bike, will feel. The satellite galaxy’s stars are much too compact to be affected by the steady stream of oncoming intergalactic gas. 

But the satellite galaxy’s own gas is not: It would be stripped away by the oncoming hot gas in a process known as “ram pressure stripping”. On the other hand, a fast-moving galaxy has no chance of pulling in a sufficient amount of intergalactic gas, to replenish its gas reservoir. The upshot is that such satellite galaxies lose their gas almost completely – and with it the raw material needed for star formation. As a result, star-formation activity would be quenched.

The processes in question take place over millions or even billions of years, so we cannot watch them happening directly. But even so, there are ways for astronomers to learn more. They can utilize computer simulations of virtual universes, programmed so as to follow the relevant laws of physics – and compare the results with what we actually observe. And they can look for tell-tale clues in the comprehensive “snapshot” of cosmic evolution that is provided by astronomical observations.

Annalisa Pillepich, a group leader at the Max Planck Institute for Astronomy (MPIA), specializes in simulations of this kind. The IllustrisTNG suite of simulations, which Pillepich has co-led, provides the most detailed virtual universes to date – universes in which researchers can follow the movement of gas around on comparatively small scales. 

IllustrisTNG provides some extreme examples of satellite galaxies that have freshly been stripped by ram pressure: so-called “jellyfish galaxies,” that are trailing the remnants of their gas like jellyfish are trailing their tentacles. In fact, identifying all the jellyfish in the simulations is a recently launched citizen science project on the Zooniverse platform, where volunteers can help with the research into that kind of freshly quenched galaxy.

But, while jellyfish galaxies are relevant, they are not where the present research project started. Over lunch in November 2019, Pillepich recounted a different one of her IllustrisTNG results to Ignacio Martín-Navarro, an astronomer specializing in observations, who was at MPIA on a Marie Curie fellowship. A result about the influence of supermassive black holes that reached beyond the host galaxy, into intergalactic space.

Such supermassive black holes can be found in the center of all galaxies. Matter falling onto such a black hole typically becomes part of a rotating so-called accretion disk surrounding the black hole, before falling into the black hole itself. This fall onto the accretion disk liberates an enormous amount of energy in the form of radiation, and oftentimes also in the form of two jets of quickly moving particles, which accelerate away from the black hole at right angles to the accretion disk. A supermassive black hole that is emitting energy in this way is called an Active Galactic Nucleus, AGN for short.

While IllustrisTNG is not detailed enough to include black hole jets, it does contain physical terms that simulate how an AGN is adding energy to the surrounding gas. And as the simulation showed, that energy injection will lead to gas outflows, which in turn will orient themselves along a path of least resistance: in the case of disk galaxies similar to our own Milky Way, perpendicular to the stellar disk; for so-called elliptical galaxies, perpendicular to a suitable preferred plane defined by the arrangement of the galaxy’s stars.

Over time, the bipolar gas outflows, perpendicular to the disk or preferred plane, will go so far as to affect the intergalactic environment – the thin gas surrounding the galaxy. They will push the intergalactic gas away, each outflow creating a gigantic bubble. It was this account that got Pillepich and Martín-Navarro thinking: If a satellite galaxy were to pass through that bubble – would it be affected by the outflow, and would its star formation activity be quenched even further?

Martín-Navarro took up this question within his own domain. He had extensive experience in working with data from one of the largest systematic surveys to date: the Sloan Digital Sky Survey (SDSS), which provides high-quality images of a large part of the Northern hemisphere. In the publicly available data from that survey’s 10th data, he examined 30,000 galaxy groups and clusters, each containing a central galaxy and on average 4 satellite galaxies.

In a statistical analysis of those thousands of systems, he found a small, but marked difference between satellite galaxies that were close to the central galaxy’s preferred plane and satellites that were markedly above and below. But the difference was in the opposite direction the researchers had expected: Satellites above and below the plane, within the thinner bubbles, were on average not more likely, but about 5% less likely to have had their star formation activity quenched.

With that surprising result, Martín-Navarro went back to Annalisa Pillepich, and the two performed the same kind of statistical analysis in the virtual universe of the IllustrisTNG simulations. In simulations of that kind, after all, cosmic evolution is not put in “by hand” by the researchers. Instead, the software includes rules that model the rules of physics for that virtual universe as naturally as possible, and which also include suitable initial conditions that correspond to the state of our own universe shortly after the Big Bang.

That is why simulations like that leave room for the unexpected – in this particular case, for re-discovering the on-plane, off-plane distribution of quenched satellite galaxies: The virtual universe showed the same 5% deviation for the quenching of satellite galaxies! Evidently, the researchers were on to something.

In time, Pillepich, Martín-Navarro and their colleagues came up with a hypothesis for the physical mechanism behind the quenching variation. Consider a satellite galaxy travelling through one of the thinned-out bubbles the central black hole has blown into the surrounding intergalactic medium. Due to the lower density, that satellite galaxy experiences less headwind, less ram pressure, and is thus less likely to have its gas stripped away. 

Then, it is down to statistics. For satellite galaxies that have orbited the same central galaxies several times already, traversing bubbles but also the higher-density regions in between, the effect will not be noticeable. Such galaxies will have lost their gas long ago.

But for satellite galaxies that have joined the group, or cluster, rather recently, location will make a difference: If those satellites happen to land in a bubble first, they are less likely to lose their gas then if they happen to land outside a bubble. This effect could account for the statistical difference for the quenched satellite galaxies.

With the excellent agreement between the statistical analyses of both the SDSS observations and the IllustrisTNG simulations, and with a plausible hypothesis for a mechanism, this is a highly promising result. In the context of galaxy evolution, it is particularly interesting because it confirms, indirectly, the role of active galactic nuclei not only heating intergalactic gas up, but actively “pushing it away”, to create lower-density regions. And as with all promising results, there are now a number of natural directions that either Martín-Navarro, Pillepich and their colleagues or other scientists can take in order to explore further.

Featured image: Virtual milky way: Gas density around a massive central galaxy in a group in the virtual universe of the TNG50 simulation. Gas inside the galaxy corresponds to the bright vertical structure: a gaseous disk. To the left and right of that structure are bubbles – regions that look like circles in this image, with markedly reduced gas density inside. This geometry of the gas is due to the action of the super massive black hole that hides at the center of the galaxy and that pushes out gas preferably in directions perpendicular to the galaxy gaseous disk, carving regions of lower density. © TNG Collaboration/Dylan Nelson

Reference: Martín-Navarro, I., Pillepich, A., Nelson, D. et al. Anisotropic satellite galaxy quenching modulated by black hole activity. Nature 594, 187–190 (2021). https://doi.org/10.1038/s41586-021-03545-9

Provided by Max Planck Gesellschaft

The Sun’s Clock: New Calculations Support And Expand Planetary Hypothesis (Planetary Science)

All cycles fit the picture: new calculations support and expand planetary hypothesis

Not only the very concise 11-year cycle, but also all other periodic solar activity fluctuations can be clocked by planetary attractive forces. This is the conclusion drawn by Dr. Frank Stefani and his colleagues from the Institute of Fluid Dynamics at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) and from the Institute of Continuous Media Mechanics in Perm, Russia. With new model calculations, they are proposing a comprehensive explanation of all important known sun cycles for the first time. They also reveal the longest fluctuations in activity over thousands of years as a chaotic process. Despite the planetary timing of short and medium cycles, long-term forecasts of solar activity thus become impossible, as the researchers in the scientific journal Solar Physics (DOI: 10.1007/s11207-021-01822-4) assert.

Solar physicists around the world have long been searching for satisfactory explanations for the sun’s many cyclical, overlapping activity fluctuations. In addition to the most famous, approximately 11-year “Schwabe cycle”, the sun also exhibits longer fluctuations, ranging from hundreds to thousands of years. It follows, for example, the “Gleissberg cycle” (about 85 years), the “Suess-de Vries cycle” (about 200 years) and the quasi-cycle of “Bond events” (about 1500 years), each named after their discoverers. It is undisputed that the solar magnetic field controls these activity fluctuations.

Explanations and models in expert circles partly diverge widely as to why the magnetic field changes at all. Is the sun controlled externally or does the reason for the many cycles lie in special peculiarities of the solar dynamo itself? HZDR researcher Frank Stefani and his colleagues have been searching for answers for years – mainly to the very controversial question as to whether the planets play a role in solar activity.

Rosette-shaped movement of the sun can produce a 193-year cycle

The researchers have most recently taken a closer look at the sun’s orbital movement. The sun does not remain fixed at the center of the solar system: It performs a kind of dance in the common gravitational field with the massive planets Jupiter and Saturn – at a rate of 19.86 years. We know from the Earth that spinning around in its orbit triggers small motions in the Earth’s liquid core. Something similar also occurs within the sun, but this has so far been neglected with regard to its magnetic field.

The researchers came up with the idea that part of the sun’s angular orbital momentum could be transferred to its rotation and thus affect the internal dynamo process that produces the solar magnetic field. Such coupling would be sufficient to change the extremely sensitive magnetic storage capacity of the tachocline, a transition region between different types of energy transport in the sun’s interior. “The coiled magnetic fields could then more easily snap to the sun’s surface,” says Stefani.

The researchers integrated one such rhythmic perturbation of the tachocline into their previous model calculations of a typical solar dynamo, and they were thus able to reproduce several cyclical phenomena that were known from observations. What was most remarkable was that, in addition to the 11.07-year Schwabe cycle they had already modeled in previous work, the strength of the magnetic field now also changed at a rate of 193 years – this could be the sun’s Suess-de Vries cycle, which from observations has been reported to be 180 to 230 years. Mathematically, the 193 years arise as what is known as a beat period between the 19.86-year cycle and the twofold Schwabe cycle, also called the Hale cycle. The Suess-de Vries cycle would thus be the result of a combination of two external “clocks”: the planets’ tidal forces and the sun’s own movement in the solar system’s gravitational field.

Planets as a metronome

For the 11.07-year cycle, Stefani and his researchers had previously found strong statistical evidence that it must follow an external clock. They linked this “clock” to the tidal forces of the planets Venus, Earth and Jupiter. Their effect is greatest when the planets are aligned: a constellation that occurs every 11.07 years. As for the 193-year cycle, a sensitive physical effect was also decisive here in order to trigger a sufficient effect of the weak tidal forces of the planets on the solar dynamo.

After initial skepticism toward the planetary hypothesis, Stefani now assumes that these connections are not coincidental. “If the sun was playing a trick on us here, then it would be with incredible perfection. Or, in fact, we have a first inkling of a complete picture of the short and long solar activity cycles.” In fact, the current results also retroactively reaffirm that the 11-year cycle must be a timed process. Otherwise, the occurrence of a beat period would be mathematically impossible.

Tipping into chaos: 1000-2000-year collapses are not more accurately predictable

In addition to the rather shorter activity cycles, the sun also exhibits long-term trends in the thousand-year range. These are characterized by prolonged drops in activity, known as “minima”, such as the most recent “Maunder Minimum”, which occurred between 1645 and 1715 during the “Little Ice Age”. By statistically analyzing the observed minima, the researchers could show that these are not cyclical processes, but that their occurrence at intervals of approximately one to two thousand years follows a mathematical random process.

To verify this in a model, the researchers expanded their solar dynamo simulations to a longer period of 30,000 years. In fact, in addition to the shorter cycles, there were irregular, sudden drops in magnetic activity every 1000 to 2000 years. “We see in our simulations how a north-south asymmetry forms, which eventually becomes too strong and goes out of sync until everything collapses. The system tips into chaos and then takes a while to get back into sync again,” says Stefani. But this result also means that very long-term solar activity forecasts – for example, to determine influence on climate developments – are almost impossible.

Featured image: Active regions galore: the sun sported about a dozen active regions over a five-day period in May, 2015. The bright, spindly strands that extend out of these active regions are particles spinning along magnetic field lines that connect areas of opposite polarity. Photo: Solar Dynamics Observatory, NASA

F. Stefani, R. Stepanov, T. Weier, Shaken and stirred: When Bond meets Suess-de Vries and Gnevyshev-Ohl, in Solar Physics, 2021 (DOI: 10.1007/s11207-021-01822-4)

Provided by HZDR

Touchless Technology Could Enable Early Detection And Treatment Of Eye Diseases That Cause Blindness (Engineering)

Non-contact laser imaging system designed to detect telltale signs of major blinding diseases

A non-contact laser imaging system could help doctors diagnose and treat eye diseases that cause blindness much earlier than is now possible.

The new technology, developed by engineering researchers at the University of Waterloo, is designed to detect telltale signs of major blinding diseases in retinal blood and tissue that typically go unseen until it is too late.

With current testing methods, diseases such as age-related macular degeneration, diabetic retinopathy and glaucoma—which have no symptoms in their early stages—are usually diagnosed only after vision is irreversibly affected.

“We’re optimistic that our technology, by providing functional details of the eye such as oxygen saturation and oxygen metabolism, may be able to play a critical role in early diagnosis and management of these blinding diseases,” said Parsin Haji Reza, director of the PhotoMedicine Labs at Waterloo.

Patented technology at the core of the new system is known as photoacoustic remote sensing (PARS). It uses multicoloured lasers to almost instantly image human tissue without touching it.

When used for eyes, the non-invasive, non-contact approach dramatically improves both patient comfort and the accuracy of test results.

The technology is also being applied by Haji Reza and researchers in his lab to provide microscopic analyses of breast, gastroenterological, skin and other cancerous tissues, and to enable real-time imaging to guide surgeons during the removal of brain tumors.

“PARS may move us beyond the current gold standard in ophthalmological imaging,” said Dr. Richard Weinstein, an ophthalmologist and co-founder of the Ocular Health Centre. “For the first time, not just in ophthalmology but in the entire medical field, diagnosis and treatment of disease could be made prior to structural change and functional loss.”

Haji Reza, a professor of systems design engineering and co-founder of startup company illumiSonics, said researchers are working with several ophthalmologists and hope to start clinical trials within two years.

A paper on the research, Functional and structural ophthalmic imaging using noncontact multimodal photoacoustic remote sensing microscopy and optical coherence tomography, appears in the journal Scientific Reports.

The research team includes graduate students Zohreh Hosseinaee, Nicholas Pellegrino, Layla Khalili and Lyazzat Mukhangaliyeva, and research assistant Nima Abbassi.

Reference: Hosseinaee, Z., Nima Abbasi, Pellegrino, N. et al. Functional and structural ophthalmic imaging using noncontact multimodal photoacoustic remote sensing microscopy and optical coherence tomography. Sci Rep 11, 11466 (2021). https://doi.org/10.1038/s41598-021-90776-5

Provided by University of Waterloo

USC Study Reveals Potential New Treatment Target For Alzheimer’s Disease (Neuroscience)

Researchers at Keck School of Medicine of USC identify a novel target related to the blood-brain barrier and a potential therapy that offers hope for slowing progression of Alzheimer’s disease in people with the APOE4 gene

Like amyloid plaque, the genetic variant APOE4 has long been associated with Alzheimer’s disease, but still little is known about the role the gene plays in the disease process.

Now, a new study published in Nature Aging not only sheds light on how the gene may instigate a cascade of pathologies that contribute to Alzheimer’s disease, but also suggests a new treatment target that might help people who carry the APOE4 gene in early and late stages of the disease. Keck School of Medicine of USC researchers found that APOE4 is associated with the activation of an inflammatory protein that causes a breakdown in the blood-brain barrier which protects the brain.

This research builds on a recent USC study that revealed APOE4 triggers leaks in the blood-brain barrier in humans, which lets toxic substances from the blood stream into the brain, damaging brain cells and disrupting cognitive functions. This process causes memory problems in patients whether or not their brain shows signs of amyloid-β, the sticky plaque peptide considered a hallmark of the disease.

The latest findings also suggest a new potential treatment to slow down or prevent the cognitive decline associated with Alzheimer’s disease in patients with the APOE4 gene, independently of amyloid-β pathology.

“We’re further focusing on therapeutics targets in blood vessels that could bring innovative treatments to people suffering from Alzheimer’s disease, both early and late stages of the disease. Current findings in mouse models might be particularly promising for treating late stage disease in the presence of advanced amyloid-β pathology,” said Berislav Zlokovic, MD, PhD, director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC.

The role of APOE4, pericytes and Cyclophilin A in Alzheimer’s disease

APOE4 has been shown to accelerate the blood-brain barrier breakdown by damaging pericytes, a layer of cells that strengthen and protect the brain capillaries which make up the blood-brain barrier. This breakdown is also associated with higher levels of Cyclophilin A, a pro-inflammatory protein, in the brain vessels of Alzheimer’s disease patients with the APOE4 gene.

Berislav Zlokovic, MD, PhD, Director of the Zilkha Neurogenetic Institute © Richard Carrasco

In this study, USC researchers focused on Cyclophilin A in mice with the APOE4 gene, which carries a high risk for Alzheimer’s disease, and mice with the APOE3 gene, which carries an average risk for Alzheimer’s disease. Cyclophilin A is found in pericytes and controls how strong the blood vessels are in maintaining the integrity of the blood-brain barrier. In the APOE4 mice, researchers found Cyclophilin A caused an enzyme that degrades blood vessels in the blood-brain barrier — matrix metalloproteinase 9 (MMP9) — to become active. This did not happen in the APOE3 gene mice.

Researchers then tried treating APOE4 mice with an inhibitor known to suppress Cyclophilin A. The inhibitor not only improved integrity in the blood-brain barrier in APOE4 mice, but also prevented development of further neuron loss and behavioral deficits. Researchers observed that the APOE4 mice treated with the inhibitor did not exhibit behavioral deficits during daily activities. This suggests that treatment targeting this pathway might have the potential to also slow down the progression of vascular and neurodegenerative disorders in people with Alzheimer’s disease who have the APOE4 gene.

“So far there has been little hope for those in the late stage of the disease, which is very hard on patients and their loved ones,” said Zlokovic. “We are excited to further study the potential that interventions focused on blood-brain barrier repair and blood vessel strength, independent of amyloid pathology, could have on slowing down or stopping neurodegeneration and cognitive decline in advanced Alzheimer’s disease.”

The inhibitor used in this study to suppress the Cyclophilin A, Debio-025, has been used in humans to treat hepatitis C, suggesting this could be a potential treatment for cognitive impairment in APOE4 carriers that show Cyclophilin A-MMP9 pathway activity in early or late disease stages.

About the study

In addition to Zlokovic, other authors on the study include Axel Montagne, Angeliki Nikolakopoulou, Mikko Huuskonen, Abhay Sagare, Erica Lawson, Divna Lazic, Sanket Rege, Alexandra Grond, Edward Zuniga, Jacob Prince, Meghana Sagare, Ching Hsu and Russell Jacobs of the Department of Research Physiology & Neuroscience and Zilkha Neurogenetic Institute at the Keck School of Medicine of USC; Samuel Barnes of the Department of Radiology at Loma Linda University; and Mary LaDu of the Department of Anatomy and Cell Biology at the College of Medicine at the University of Illinois at Chicago.

This study was supported by the National Institutes of Health (R01NS034467, R01AG023084, R01AG039452 and 1R01NS100459), Cure Alzheimer’s Fund and the Foundation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease reference number 16 CVD 05.

Featured image: Activation of cyclophilin A (CypA; red upper panels) leads to activation of MMP9 (red lower panels) in CD13+-pericytes (green) in brain capillaries of APOE4 humanized Alzheimer’s disease (AD) mice with advanced amyloid-beta pathology. The images on the right, perpendicular to those on the left, show an overlap of of CypA or MMP9 with CD13+-pericytes: bar, 10 μm. Lectin+-endothelium is labeled blue indicating cortical capillaries. © Angeliki Nikolakopoulou, PhD

Reference: Montagne, A., Nikolakopoulou, A.M., Huuskonen, M.T. et al. APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β. Nat Aging 1, 506–520 (2021). https://doi.org/10.1038/s43587-021-00073-z

Provided by Keck School of Medicine

Plant-based Diet Protects From Hypertension, Preeclampsia (Food)

A plant-based diet appears to afford significant protection to rats bred to become hypertensive on a high-salt diet, scientists report. When the rats become pregnant, the whole grain diet also protects the mothers and their offspring from deadly preeclampsia.

Although we have all heard to avoid the salt shaker, an estimated 30-50% of us have a significant increase in blood pressure in response to high-salt intake, percentages that are even higher and more impactful in Blacks.

The two new studies provide more evidence that the gut microbiota, which contains trillions of microorganisms that help us digest food and plays a key role in regulating the response of our immune system, is also a player in the unhealthy response to salt, investigators at the Medical College of Georgia and Medical College of Wisconsin report in the journals ACTA PHYSIOLOGICA and Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health.

The findings provide more evidence of the “potential power” of nutritional intervention to improve the gut microbiota, and consequently our long-term health, says Dr. David L. Mattson, chair of the MCG Department of Physiology, Georgia Research Alliance Eminent Scholar in Hypertension and senior author on the two studies.

They result from the unexpected observation that the protection works even in a well-established model of salt-sensitive hypertension: The Dahl salt sensitive rat.

As their name indicates, these rodents are bred to develop hypertension and progressive kidney disease on a high-salt diet. In 2001, the Medical College of Wisconsin shared their colony of Dahl SS rats, who were fed a milk-based protein diet, with Charles Rivers Laboratories. Once the rats arrived as Charles River Laboratories, headquartered in Wilmington, Massachusetts, they were switched to a grain-based diet. Both diets are relatively low in sodium, although the protein, or casein-based, diet actually has a little less salt.

It was soon noted that when high-salt content was added to their diet, the relocated rodents developed significantly less high blood pressure and related kidney damage than the rat colonies that remained in Wisconsin.

“People ordered them and used them with the idea that they were going to study hypertension and they developed next to none,” Mattson says. More than a decade of research documented these differences, Mattson and his colleagues at MCG and MCW write, and now has shown them that developing salt-sensitive hypertension isn’t just about sodium consumption.

“The animal protein amplified the effects of the salt,” says Mattson, a longtime hypertension researcher, who along with Dr. Justine M. Abais-Battad, physiologist, and postdoc Dr. John Henry Dasinger, came to MCG from Wisconsin two summers ago.

“Since the gut microbiota has been implicated in chronic diseases like hypertension, we hypothesized that dietary alterations shift the microbiota to mediate the development of salt-sensitive hypertension and renal disease,” they write in the journal ACTA PHYSIOLOGICA.

The gut microbiome is designed to metabolize what we eat, break it down and put it in a form that gives us nutrition, first author Abais-Battad says, and reciprocally it reflects what we eat.

When they looked at the microbiomes in the rats: “Sure enough, they were different,” she says.

They sequenced the genetic material of both rat colonies and found they were “virtually identical,” but their response to a high-salt diet was anything but, Mattson says.

As they anticipated at this juncture, the Wisconsin rats developed renal damage and inflammation — both indicators of high blood pressure — but on the same high-salt diet, the Charles River rats experienced significantly less of these unhealthy results. The distinct differences they saw in their microbiota, reflected the difference in disease incidence and severity.

When they gave the protected rats some of the distinctive gut microbiota from the Wisconsin rats, via fecal transplant, the rats experienced increases in blood pressure, kidney damage and in the number of immune cells moving into the kidneys, organs which play a huge role in blood pressure regulation by regulating fluid balance, in part by determining how much sodium is retained. It also changed the composition of their microbiota.

But when they shared the microbiota of the protected rats with the Wisconsin rats, it didn’t have much impact, potentially because the new microorganisms couldn’t flourish in the face of the animal-based protein diet, the scientists say.

Preeclampsia is a potentially lethal problem during pregnancy where the mother’s blood pressure, which typically was normal before, soars and organs like the kidneys and liver show signs of damage. There is evidence that even on a low-salt diet, Dahl salt sensitive rats are inclined to develop preeclampsia.

To look at the impact of diet in this scenario, the Dahl SS rats were kept on their respective plant- or animal-based protein diet, which again are each relatively low salt, and both groups had three separate pregnancies and deliveries.

Rats on the whole wheat based-chow were protected from preeclampsia while about half of the rats on the animal-based casein diet developed this significant complication of pregnancy, says Dasinger, first author on the preeclampsia study. They experienced a significant increase in the protein spilled into their urine, an indicator of kidney trouble, which worsened with each pregnancy; increased inflammation, a driver of high blood pressure; increased pressure inside the renal artery; and showed significant signs of kidney destruction when the organs were studied on follow up. They died of problems like stroke, kidney disease and other cardiovascular problems.

“This means that if mom is careful with what she eats during pregnancy, it will help during the pregnancy, but also with her long-term health and could provide protective effects for her children,” Dasinger says. The scientists note this reinforces the message that physicians and scientists alike have been sending mothers-to-be for decades.

They plan to look more directly at the impact of diet on offspring and whether protection is passed to the babies through breast milk, Dasinger says. Since they know that the function of immune cells is affected by diet, they also want to look further at the function of the immune cells that show up and already have some evidence that T cells, drivers of the immune response, are a factor in the development of preeclampsia.

The work Abais-Battad, Dasinger and Mattson already have done shows that a key difference the different diets yield is the protein-based diet results in production of more proinflammatory molecules, where the plant-based diet actually seems to suppress these factors.

They also are further exploring the impact of diet of the renin-angiotensin system, which helps regulate blood pressure. They also want to better dissect the blood pressure-raising bacteria and the factors they produce.

High blood pressure is the largest modifiable risk factor for development of cardiovascular disease, and, according to the newest guidelines from groups like the American Heart Association, which say a systolic, or top number of 120+ is elevated and top numbers of 130-139 is stage one hypertension, nearly half of us are hypertensive. Diet — including a high-salt diet — is one of the top modifiable risk factors for high blood pressure and cardiovascular disease, the scientists say. Hypertensive humans and animals alike have been found to have an unbalanced, less diverse gut microbiota than those with normal blood pressure.

The research was supported by the National Heart, Lung and Blood Institute, the American Heart Association and the Georgia Research Alliance.

Read the studies here and here.

Featured image: (from left) Drs. John Henry Dasinger, Justine M. Abais-Battad and David L. Mattson. © Michael Holahan, Augusta University

Provided by Medical University of Georgia at Augusta University

Study Presents New Species of Bizarre, Extinct Lizard Previously Misidentified As A Bird (Paleontology)

An international research team has described a new species of Oculudentavis, providing further evidence that the animal first identified as a hummingbird-sized dinosaur was actually a lizard.

The new species, named Oculudentavis naga in honor of the Naga people of Myanmar and India, is represented by a partial skeleton that includes a complete skull, exquisitely preserved in amber with visible scales and soft tissue. The specimen is in the same genus as Oculudentavis khaungraae, whose original description as the smallest known bird was retracted last year. The two fossils were found in the same area and are about 99 million years old.

Researchers published their findings in Current Biology today.

The team, led by Arnau Bolet of Barcelona’s Institut Català de Paleontologia Miquel Crusafont, used CT scans to separate, analyze and compare each bone in the two species digitally, uncovering a number of physical characteristics that earmark the small animals as lizards. Oculudentavis is so strange, however, it was difficult to categorize without close examination of its features, Bolet said.

“The specimen puzzled all of us at first because if it was a lizard, it was a highly unusual one,” he said in an institutional press release.

Bolet and fellow lizard experts from around the world first noted the specimen while studying a collection of amber fossils acquired from Myanmar by gemologist Adolf Peretti. (Note: The mining and sale of Burmese amber are often entangled with human rights abuses. Peretti purchased the fossil legally prior to the conflict in 2017. More details appear in an ethics statement at the end of this story).

Herpetologist Juan Diego Daza examined the small, unusual skull, preserved with a short portion of the spine and shoulder bones. He, too, was confused by its odd array of features: Could it be some kind of pterodactyl or possibly an ancient relative of monitor lizards?

“From the moment we uploaded the first CT scan, everyone was brainstorming what it could be,” said Daza, assistant professor of biological sciences at Sam Houston State University. “In the end, a closer look and our analyses help us clarify its position.”

Major clues that the mystery animal was a lizard included the presence of scales; teeth attached directly to its jawbone, rather than nestled in sockets, as dinosaur teeth were; lizard-like eye structures and shoulder bones; and a hockey stick-shaped skull bone that is universally shared among scaled reptiles, also known as squamates.

The team also determined both species’ skulls had deformed during preservation. Oculudentavis khaungraae’s snout was squeezed into a narrower, more beaklike profile while O. naga’s braincase – the part of the skull that encloses the brain – was compressed. The distortions highlighted birdlike features in one skull and lizard-like features in the other, said study co-author Edward Stanley, director of the Florida Museum of Natural History’s Digital Discovery and Dissemination Laboratory.

Oculudentavis naga, top, is in the same genus as Oculudentavis khaungraae, bottom, a specimen whose controversial identification as an early bird was retracted last year. Both specimens’ skulls deformed during preservation, emphasizing lizardlike features in one and birdlike features in the other. © Edward Stanley of the Florida Museum of Natural History/Peretti Museum Foundation/Current Biology

“Imagine taking a lizard and pinching its nose into a triangular shape,” Stanley said. “It would look a lot more like a bird.”

Oculudentavis’ birdlike skull proportions, however, do not indicate that it was related to birds, said study co-author Susan Evans, professor of vertebrate morphology and paleontology at University College London.

“Despite presenting a vaulted cranium and a long and tapering snout, it does not present meaningful physical characters that can be used to sustain a close relationship to birds, and all of its features indicate that it is a lizard,” she said.

While the two species’ skulls do not closely resemble one another at first glance, their shared characteristics became clearer as the researchers digitally isolated each bone and compared them with each other. The differences were minimized when the original shape of both fossils was reconstructed through a painstaking process known as retrodeformation, conducted by Marta Vidal-García from the University of Calgary in Canada.

“We concluded that both specimens are similar enough to belong to the same genus, Oculudentavis, but a number of differences suggest that they represent separate species,” Bolet said.

In the better-preserved O. naga specimen, the team was also able to identify a raised crest running down the top of the snout and a flap of loose skin under the chin that may have been inflated in display, Evans said. However, the researchers came up short in their attempts to find Oculudentavis’ exact position in the lizard family tree.

“It’s a really weird animal. It’s unlike any other lizard we have today,” Daza said. “We think it represents a group of squamates we were not aware of.”

The Cretaceous Period, 145.5 to 66 million years ago, gave rise to many lizard and snake groups on the planet today, but tracing fossils from this era to their closest living relatives can be difficult, Daza said.

Amber can exquisitely preserve small forest animals that would have otherwise decomposed. CT scans of this fossilized Oculudentavis naga showcase the specimen’s scales, skin and soft tissue. © Adolf Peretti/Peretti Museum Foundation/Current Biology

“We estimate that many lizards originated during this time, but they still hadn’t evolved their modern appearance,” he said. “That’s why they can trick us. They may have characteristics of this group or that one, but in reality, they don’t match perfectly.”

The majority of the study was conducted with CT data created at the Australian Centre for Neutron Scattering and the High-Resolution X-ray Computed Tomography Facility at the University of Texas at Austin. O. naga is now available digitally to anyone with Internet access, which allows the team’s findings to be reassessed and opens up the possibility of new discoveries, Stanley said.

“With paleontology, you often have one specimen of a species to work with, which makes that individual very important. Researchers can therefore be quite protective of it, but our mindset is ‘Let’s put it out there,'” Stanley said. “The important thing is that the research gets done, not necessarily that we do the research. We feel that’s the way it should be.”

While Myanmar’s amber deposits are a treasure trove of fossil lizards found nowhere else in the world, Daza said the consensus among paleontologists is that acquiring Burmese amber ethically has become increasingly difficult, especially after the military seized control in February.

“As scientists we feel it is our job to unveil these priceless traces of life, so the whole world can know more about the past. But we have to be extremely careful that during the process, we don’t benefit a group of people committing crimes against humanity,” he said. “In the end, the credit should go to the miners who risk their lives to recover these amazing amber fossils.”

Other study co-authors are J. Salvador Arias of Argentina’s National Scientific and Technical Research Council (CONICET – Miguel Lillo Foundation); Andrej Cernansky of Comenius University in Bratislava, Slovakia; Aaron Bauer of Villanova University; Joseph Bevitt of the Australian Nuclear Science and Technology Organisation; and Adolf Peretti of the Peretti Museum Foundation in Switzerland.

A 3D digitized specimen of O. naga is available online via MorphoSource. The O. naga fossil is housed at the Peretti Museum Foundation in Switzerland, and the O. khaungraae specimen is at the Hupoge Amber Museum in China.

The specimen was acquired following the ethical guidelines for the use of Burmese amber set forth by the Society for Vertebrate Paleontology. The specimen was purchased from authorized companies that are independent from military groups. These companies export amber pieces legally from Myanmar, following an ethical code that ensures no violations of human rights were committed during mining and commercialization and that money derived from sales did not support armed conflict. The fossil has an authenticated paper trail, including export permits from Myanmar. All documentation is available from the Peretti Museum Foundation upon request.

Featured image: Oculudentavis naga, as depicted in this artist’s reconstruction, was a bizarre lizard that researchers initially struggled to categorize. They are still unsure of its exact position in the lizard family tree. © Stephanie Abramowicz/Peretti Museum Foundation/Current Biology

Reference: Arnau Bolet et al., “Unusual morphology in the mid-Cretaceous lizard Oculudentavis”, Current Biology, 2021. DOI:https://doi.org/10.1016/j.cub.2021.05.040

Provided by Florida Museum

New Technology Paves The Way For Vaccination Against Cancer (Medicine)

With a new method, researchers at Uppsala University want to teach our immune system to identify tumors and create the T cells to destroy them. “It is inspiring to see something so innovative originate in Sweden,” says Kristian Sandberg, head of SciLifeLab’s Drug Discovery and Development Platform.

Immunotherapy as a cancer treatment – to utilise and strengthen the body’s immune system against tumor cells – took another important step as Sara Mangsbo, research director in immune-oncology, presented the results of her many years of collaboration with SciLifeLab on a new platform technology with potential for individual and cost-effective cancer care.

“Immunotherapy is experiencing tremendous success, but still faces the challenge to increase the number of tumor-specific T cells and to make them seek out and destroy cancer cells. We have chosen a partly alternative strategy and developed a method reminiscent of vaccination, where we via an injection make the tumor visible to the immune system and accelerate the production of the exact T cells required,” says Sara Mangsbo, Associate Senior Lecturer at Uppsala University.

The strategy, named Antibody Drug Affinity Conjugate (ADAC), is based on creating synthetic fragments of proteins, similar to those found in the tumor and injecting them into the patient. This exposes the tumor to the immune system, which consequently begins to produce completely new, tumor-specific T cells, which in turn lead the already existing T cells to identify and destroy the tumor.

“Our key scientific progress is that ADAC enables us to extend the stability of the peptides in the body and our development of a generic method to direct them in the body, control the uptake into intended cells and thereby stimulate an increase in the number of T cells. This is a breakthrough that would not be possible without the invaluable support we have received at SciLifeLab’s Drug Discovery and Development Platform,” states Sara Mangsbo.

SLL handing over research documentation
Sara Mangsbo receiving research documentation © Uppsala University

The Drug Discovery and Development Platform at SciLifeLab is a national resource supporting pharmaceutical research. With operations at five Swedish universities – and joint representation via Uppsala University – the platform assists academic researchers in developing innovative therapeutic concepts and provides resources and expertise that enable research that would otherwise not be possible in our country.

“The strength of Sara Mangsbo’s idea was obvious already at our first meeting and the approach she presented was both sophisticated and far-sighted. Now we have joined forces for close to five years which have been both stimulating and fun. Sara and her team are young and hungry, but also perceptive in their ambitions. Now they have an innovation with the potential to be quite a game changer, and it is extremely inspiring to see something so innovative originate in Sweden,” says Kristian Sandberg, head of SciLifeLab’s Drug Discovery and Development Platform.

In parallel with preclinical research at Uppsala Biomedical Center, the group has already prepared the transfer to clinical studies in collaboration with Testa Center, an innovation environment and test bed for biological production located at Cytiva’s site in Uppsala. Here, researchers at Uppsala University have access to high-quality equipment and expertise for upscaling biological processes, making it possible to test the potential of new ideas at an early stage, thus, reducing the risks along the way to the finished product.

Team Mangsbo on site at Testa Center
Team Mangsbo at the Testa Center lab

“Specifying a biomedical production process would require significant resources from a single research team. Sara Mangsbo contacted us at an early stage, and with our support, her team – reinforced with several skilled students – has in cost- and time-efficient ways tried and evaluated upscaling solutions of a tetravalent bispecific antibody. It has been a rewarding collaboration, and as our agreement with Uppsala University recently extended for another two years, we look forward to taking on new exciting projects,” says Jesper Hedberg, operations manager at Testa Center.

Next, Sara Mangsbo will continue to develop her method within the newly started company Strike Pharma AB, in which she unites researchers from, among others, Uppsala University and KTH. Strike Pharma AB has chosen to establish itself at Green Innovation Park, an innovation environment at the Swedish University of Agricultural Sciences, fostering cooperation, new thinking and sustainable innovations.

“We are convinced that this is the right environment for us to take the next step in the design and production of the specific antibody we have developed. If we do reach all the way, it can significantly shorten the path to treat cancer, but we also identify great potential within viral diseases. In Strike Pharma AB, we have assembled a very competent line-up and the funding to take us a good distance along the way, so the future definitely looks promising,” says Sara Mangsbo.

Featured image: Sara Mangsbo, research director in immuno-oncology, on site at SciLifeLab. Photograph: Mikael Wallerstedt

Provided by Uppsala University